ABC of HIV/AIDS and Present Status of Vaccines Shisong Jiang M.D.
Ph.D.
1.
History 1981, 5 cases of PCP were found in homosexual gay men in the USA. 1982, more cases were found in more people in more countries. 1983, the virus was first isolated in Pasteur Institute in France. 1984, National Cancer Institute of NIH in the USA also isolated the virus and a diagnosis kit was made. 1986, in Africa, another kind of HIV, HIV-2 was found. …… 2.
Epidemiology (1) In western countries, the disease has not been stopped but is no longer out of control. l The availability of anti-HIV drugs has dramatically reduced the deaths caused by HIV. l Prevention campaigns of promoting condom use and awareness of AIDS have an effect on the stability of the disease. l However, the disease is still spreading, especially in low educated, poor, and unemployed populations, HIV prevalence is still high (e.g. 2% in American black males in the USA). l Mode of transmission: Heterosexual/homosexual and drug users. (2) In developing countries, HIV/AIDS is a very serious problem. Africa: the
world epicenter. l High prevalence. l In some of the countries, AIDS is the leading cause of adult deaths. l Mode of transmission: Heterosexual transmission, blood transmission, mother-to-child. l Risk factors contribute to the AIDS prevalence: Urbanization – increase of prostitution. Modernization – population movement. Political changes, wars etc.
Asia: HIV/AIDS developing zone. l In the first decade of epidemic, only 855 cases were reported in Asia. l From the second decade of epidemic, HIV/AIDS developed very fast, firstly in Thailand, India, Vietnam and Myanmar. l Mode of transmission: multiple transmission routes include sexual, i.v. drug user and blood transmission. (3) Factors that drive the epidemic l Migration – example of South African miners. l Political turmoil and wars of ethnic conflict – example of Rwanda refugee camps. l Risky behaviours – example of Cambodian soldiers. (4) Outcomes of HIV/AIDS epidemic: l Life expectancy greatly reduced – by more than 17 years in some African countries. l Endanger the survival of children. l Destroying economy. 3.
HIV: the etiological agent of AIDS (1) Characteristics: l HIV belongs to a class of virus known as retrovirus. l Distinguishing feature: the presence of a virally encoded enzyme – reverse transcriptase. l Reverse transcriptase transcribes the viral genomic RNA into a DNA copy that ultimately integrates into the host cell genome. (2) Structure l Outer membrane: similar to that of host cell membrane but inserted with viral proteins: gp120 and gp41. l Core: 2 single chain RNA surrounded by 2 nucleus capsid proteins: p17 and p24. l Enzymes: reverse transcriptase, integrase and protease. (3) Replication l Enters host cells: host cells are kinds of cells with CD4 molecules on the surface. l Receptors on the host cells: there are two: CD4 and chemokine receptors – when viral gp120 binds to the host cell receptor (CD4 and chemokine receptors), the viral enzymes and RNA are squeezed into the host cell cytoplasma. l Reverse transcription: RNA is transcribed to DNA under the effect of reverse transcriptase. The virus now (with DNA) is called provirus. (the anti-HIV drugs such as AZT, ddC, ddI and 3Tc take effect at this stage.) Viral mutation: due to the infidelity of the reverse transcriptase, there exist 9 strains of HIV-1(A-I). Even in the same bodies, HIV can mutate into many different strains. l Integration: proviral DNA enters nucleus and integrates into host’s genome. l Transcription and translation: eventually viral proteins are synthesised. l Budding out. (4) Pathogenesis l Immediately following infection with HIV: a burst of virus replication with levels as high as 106 RNA copies/ml. Peaks at 4-8 weeks and then drops by many logs, sometimes to undetectable levels even without treatment. CD4 count drops at first then rises back to normal. Immunity induced: humoral (antibodies) and cellular (CTL, T helper) immunity that contain viral replication. l During the asymptomatic phase (up to more than 10 years): immune response continues to contain viral replication, CD4 count remains high and viral load is low. However the virus is able to evade immunity and replication in lymph nodes. It does this by: a. Integration of proviral DNA into the infected cell genome. b. Rapid viral mutation both because of the low fidelity of reverse transcriptase and escape from specific immune responses (immune selection). c. Immune suppression by viral proteins such as gp120 and tat. l During the symptomatic phase of disease (AIDS): there is a decline in immune competence reflected by a decrease in the numbers of CD4 cells (<200/mm3); rapid emergence and replication of escaped viruses which produce an imbalance of the “set point” between the immune response and virus growth. The generalised decline in immunocompetence leads to the emergence of opportunistic infections, growth of tumours and finally to death. 4.
Vaccines against HIV (1) The importance of develop an effective vaccine: l More than 95% of all new infections are in developing countries, making HIV/AIDS among the most serious threat not only to global health, but also to global development. l Prevention programs – including education, condom and clean needle distribution and peer counselling – have slowed the spread of HIV, but have not stopped it. l Treatment advances have yielded important new AIDS therapies, but the cost and complexity of their use put them out of reach for most people in the countries where they are needed the most. In industrialized nations where drugs are more readily available, side effects and increased rates of viral resistance have raised concerns about their long-term use. (2) The problems that hamper the development of an effective vaccine: l It is not clear which immune responses against HIV are necessary to confer protective immunity. That no one has been cured of AIDS makes it exceedingly difficult for scientists to identify the mechanisms or correlates for immunity to the virus. l There is no ideal animal model for HIV/AIDS. Animal models are needed to test the efficacy and safety of different vaccine strategies for eliciting protective immunity against HIV. l HIV has multiple routes and forms of transmission. HIV is transmitted sexually, intravenously, or from mother to foetus, and can infect either as “free” virus particles or more stealthily within infected cells. A man whose blood contains no detectable virus, for example, may still carry infected cells in his semen and be able to transmit infection. An effective vaccine may require stimulating all major immune responses including humoral and cellular and local (e.g. mucosal immune responses at site of infection). l HIV has multiple sub-types or clades, across the globe, and even individual sub-types mutate quickly. l HIV infects the immune system itself, incorporating its own genetic material into key regulators of the human immune system and rapidly establishing reservoirs of HIV genetic material that may remain for years. (3) Ideal characteristics of an vaccine l Efficacy in preventing transmission by mucosal and parental routes l Safe: with minimal risk of adverse reactions. l Single dose administration l Long-lived effect resulting in protection many years after vaccination. l Low cost, allowing widespread vaccination in developing countries. l Stability and ease of administration. l Ability to induce protection against infection with diverse viral isolates. (4) State of current AIDS vaccine research l Recombinant subunit vaccines. l DNA vaccines l Live recombinant viral vector vaccines. l Live recombinant bacterial vector vaccines. l Live-attenuated vaccines. l Shole-inactivated vaccines. l Virus-like particle vaccines. l Synthetic peptide vaccines.
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